This Mentored Patient-Oriented Research Career Development Award (K23) will provide additional education and training for Dr. Sarah Janicki to establish herself as a clinical translational scientist in the hormonal mediators of cognitive decline and Alzheimer's disease (AD). An integrated multidisciplinary didactic and practical training program has been developed to allow Dr. Janicki to accomplish the following goals: 1) extend her training in advanced methods in the genetic epidemiology of aging; 2) learn and use longitudinal data analytic techniques; 3) develop expertise in neuromorphometric analytic techniques of structural MRI data; 4) transition to an independent career as a clinical translational scientist. Dr. Janicki's training program is supported by committed and enthusiastic mentorship from a panel of renowned experts in the genetics, epidemiology, cognitive assessment and neuroimaging of AD, and benefits from an outstanding intellectual environment, opportunities for career growth, and substantial institutional commitment. The objectives of the proposed research plan are to determine the contribution of estrogen biosynthetic pathway gene variants to cognitive decline, and to employ neuroimaging analyses to determine the underlying neurobiological pathways through which polymorphisms in these genes affect cognitive decline in elderly men and women of different ethnicities. Investigations in the neuropathology, neuroimaging, and neuropsychological studies of AD suggest that it is an estrogen-sensitive disease. Many prior studies evaluating the effect of estrogen on cognitive decline and brain morphology in the elderly have used study populations receiving exogenous estrogen supplementation, since age-related declines in endogenous hormones do not allow accurate assessment of estrogen status. However, hormone replacement therapy may have different effects on brain morphology than does lifelong hormone exposure due to composition and administration late in life. This study uses variants in genes of known estrogen receptor and biosynthetic function (ESR1, ESR2, CYP17, CYP19, and HSD17B1) as instrumental variables to estimate the effects of single nucleotide polymorphisms (SNPs) on changes in neuropsychological cognitive assessments and structural brain outcomes. The study population includes elderly men and women from the Washington Heights-Inwood Community Aging Project (WHICAP) and the Alzheimer's disease Neuroimaging Initiative (ADNI). Confirmatory analyses of significant findings will be performed in the Rotterdam Study (RS). Exploratory aims will examine how the effects of estrogen SNPs may vary by ethnicity due to socioeconomic and cerebrovascular risk factors associated with risk for cognitive decline. This study will lay the groundwork for future R01 grant applications identifying mechanisms of hormone action that direct areas of intervention in AD. This application directly supports the National Institute on Aging's proposed mission to conduct genetic and biological research related to diseases associated with aging, its objective to understand health differences and inequities associated with race, ethnicity, and gender among older adults, and its stated commitment to foster the development of clinician scientists in aging.